PROJECT SUMMARY / ABSTRACT For hearing, as for other senses, higher-level processing improves with attention-related release of the neurotransmitter acetylcholine and activation of nicotinic acetylcholine receptors (nAChRs) in the brain. Similarly, auditory-cognitive function is enhanced by systemic administration of nicotine to activate nAChRs, impaired by pharmacological blockade of nAChRs, and progressively diminished by disease-induced loss of nAChRs (e.g., in Alzheimer’s disease) that reduces the efficacy of endogenous acetycholine. It is widely agreed, therefore, that nAChRs are important for sensory-cognitive function. As a result, selective nicotinic agonists are being developed as treatments for cognitive disorders; however, to date these are only moderately successful and further progress requires a better understanding of how nAChRs regulate cortical processing. This project will test the hypothesis that nicotine produces its cognitive-enhancing effects by “sharpening” neural representations in two key regions, primary auditory (A1) and prefrontal (PFC) cortex, and that nicotine’s effects depend on activating a2 nAChRs located on inhibitory neurons that can be identified by the protein marker, vasoactive intestinal peptide (VIP). Aim 1 will determine how nAChRs regulate neural circuits in mouse A1 and PFC using in vitro brain slices and in vivo electrophysiological recordings. The use of transgenic mouse lines will enable recordings from identified neurons, including VIP neurons, and recordings from mice with a2 nAChRs “knocked out” or made hypersensitive. Aim 2 will determine how nicotine alters the activity of A1 and PFC neurons during auditory-cued behavior using high-density single-cell recordings in rats and mice performing a novel auditory-sequence memory task. Again, nicotine effects will be compared across wild-type, a2 knock-out and a2 hypersensitive mice. Aim 3 will use chemogenetic techniques to determine if suppression of VIP neurons or a2 nAChRs blocks nicotine’s effects on neural processing, in vitro and in vivo, and behavioral performance. This project will advance the understanding of nAChRs in auditory-cognitive function and the specific involvement of VIP interneurons and a2 nAChRs in A1 and PFC. Confirmation of an important role will guide development of more effective and selective drug therapies to enhance auditory- cognitive function.

PROJECT NARRATIVE The drug nicotine enhances auditory-cognitive function because it “hijacks” the brain’s endogenous system for directing attention to important sounds (for example, understanding speech in a noisy environment). This project seeks to determine if one kind of nicotine receptor (a2 subtype) and one kind of neuron (VIP) in two key regions of the cerebral cortex (auditory cortex and prefrontal cortex) play essential roles in nicotine’s effects. The long-term goal is to understand brain mechanisms of auditory processing and guide development of novel drug treatments for auditory-cognitive disorders.